1. Field of the Invention
The present invention relates to the improvement of surgical techniques and tissue-protective surgical solutions.
2. Discussion of the Prior Art
Adhesions of the tissues and organ surfaces involved in surgery occasioned by manipulative trauma of the tissue surfaces during the surgery and other causes such as drying and ischemic trauma constitute one of the most serious post-operative complications of surgical procedures.
Although a variety of techniques have been proposed to reduce adhesions, the problem continues to plague the art and seriously compromise even the finest and most scrupulously performed surgeries. Prior attempts to alleviate the problem and the disappointing results attendant therewith are described by Davis et al, Surgery, Vol. 2, p. 87 (1937); Gozalez, Surgery, Vol. 26, p. 181 (1949); Hunter et al, J. Bone Joint Surg., Vol. 53A, p. 829 (1971); Ellis, Surg. Gynecol. Obst., Vol. 133, pp. 497-511 (1971); Lindsay et al, In Verdan, C. (ed.); Tendon Surgery of the Hand, Lond, Churchill Livingstone, pp. 35-39 (1979); Potenza, J. Bone Joint Surg., Vol. 45A, p. 1217 (1963); Verdan, J. Bone Joint Surg., Vol. 54A, p. 472 (1972); St. Onge et al, Clin. Orthop., Vol. 148, pp. 259xe2x80x94275 (1980); Thomas et al, Clin. Orthop., Vol. 206, pp. 281-289 (May, 1986); and Weiss et al, Bull. Hosp. Jt. Dis. Orthop. Inst., Vol. 46(1), pp. 9-15 (1986).
Goldberg et al [Arch. Surg., Vol. 115, pp. 776-780 (1980)] describe the use of certain hydrophilic polymer solutions (Povidone polyvinylpyrrolidone K-30 PVP and dextran) to coat tissue exposed to drying and/or manipulative peritoneal trauma, as well as the surgical articles, etc. which contact the tissue before and during surgery to prevent adhesions. Although the materials and methods of Goldberg et al showed some improvement over other research studies in which hydrophilic polymer solutions were used to attempt to reduce the incidence of surgical adhesions, there still exists a significant need for improvement.
A distinct disadvantage associated with the materials and methods of Goldberg et al and other prior art which has shown some benefit is the required use of highly concentrated solutions of the polymeric materials which makes practical use in surgery very difficult. Concentrated polymer solutions (greater than about 10-15%), for example, the 25% PVP and dextran solutions used by Goldberg et al, become sticky due to drying during surgery on the surfaces of tissue, surgeons"" gloves, instruments, etc. This can seriously interfere with normal surgical procedures. High concentrations of PVP (K-30xe2x80x94molecular weight about 40,000) and dextran (molecular weight about 300,000) were required to achieve even some degree of tissue protection. Many studies prior to the report of Goldberg et al used lower concentrations of PVP, dextran or other water-soluble polymers which were even more ineffective. For example, Ellis [supra] stated that xe2x80x9cuse of PVP was accompanied by a slightly greater incidence of adhesionsxe2x80x9d in a rat peritoneal adhesions study. He also stated that because xe2x80x9csuch macro-molecular solutions as plasma or dextran are known to be absorbed rapidly through functional lacunas on the under surface of the diaphragm . . . it is therefore probable that any effect of PVP or any other macromolecular solution introduced into the peritoneal cavity could only be transitory.xe2x80x9d In the study by Berquist et al [Eur. Surg. Res., Vol. 9, p. 321 (1977)] using 10% dextran-70 (molecular weight 70,000) and 1% hyaluronic acid (molecular weight unknown) as a post-coating at the completion of surgery, it was reported that there was xe2x80x9cno difference between control and treated groupsxe2x80x9d for adhesions in rat and rabbit studies. Even attempts to use the relatively low molecular weight dextran-70 at very high concentrations (32%) based on suggestions of some beneficial effect in reducing genital tract adhesions in female rabbits [Neuwirth et al, Am. J. Obstet. Gynecol., Vol. 121, p. 420 (1974)] have not proven very successful. A commercial 32% (w/v) solution of dextran-70 was introduced as a hysteroscopy fluid about 1984, but recent studies have shown xe2x80x9cno effect in reducing adhesionsxe2x80x9d using 32% dextran [Hadick et al, Military Medicine, Vol. 152, p. 144 (1987)].
Moreover, the use of such high concentrations may increase the expense of the surgical solutions and poses problems in preparing, purifying, stabilizing and storing solutions of such highly concentrated and often viscous solutions. For example, 32% dextran tends to crystallize xe2x80x9cwhen subjected to temperature variations or when stored for long periodsxe2x80x9d [data sheet for commercial 32% dextran-70 solution].
Although the studies reported by Goldberg et al indicated some modest improvement in preventing adhesions using 25% PVP (molecular weight 40,000) and a slight improvement with 25% dextran (molecular weight 300,000) even using a surgical method involving coating of tissues and surgical implements before surgical manipulation, the materials and surgical solutions used were clearly impractical for clinical use in surgery.
In U.S. Pat. No. 5,080,893 (and in U.S. Pat. No. 5,140,016 and application Ser. No. 07/750,840 filed Aug. 29, 1991, supra), there are described improved methods, techniques and compositions for preventing surgical adhesions in surgery.
Surgical adhesions, however, are only one of the several types of complications which arise from the damage inflicted to tissue during surgical procedures. In addition to the formation of post-operative adhesions, tissue trauma during surgery can lead to a host of other potentially serious complications during and following surgical procedures, including:
(1) excessive blood vessel damage with increased bleeding during surgery and with greater risk of post-operative hemorrhage;
(2) enhancement of (acute) post-operative inflammation with prolongation of healing and damage to adjacent healthy tissues, as well as increased potential for chronic prolonged inflammation with associated secondary complications, pain, etc.;
(3) compromised wound healing with excessive scar tissue, of particular importance in orthopedic and plastic surgery;
(4) damage to organs and tissues which can result in impaired organ function, i.e., kidneys, liver, heart, lungs, etc.;
(5) blood vessel damage which can reduce blood supply with partial ischemia of muscle tissues and organs, leading to compromised function of muscle and vital organs, which is a life-threatening situation for heart muscle damage; and
(6) increased susceptibility to acute and chronic 15infections due to preferential adherence and growth of pathogens on damaged tissue sites (post-operative staph and pseudomonas infections) with increased difficulty in treatment, slower recovery and greater chance of life-threatening systemic sepsis.
All of the above tissue damage related complications can result in longer hospitalization, patient discomfort, greater risk of morbidity and mortality, greater incidence of re-hospitalization and corrective surgery with associated patient risks, and higher health care costs.
Desiccation and abrasion tissue damage during surgery can lead to a variety of pathological surgical and post-operative complications. Damage due to desiccation and abrasion of the ovaries often results in formation of a thin fibrous membrane over the surface of the organ. Often this membrane is difficult to see with the unaided eye, yet it can act as a physical barrier to prevent transport of an egg to the Fallopian tube, thus preventing fertilization.
Prosthetic devices and implants such as heart valves, ventricular assists, vascular grafts, ligaments, tendons, corneas, skin grafts, muscle grafts, etc., which are derived entirely or in part from animal or human tissue or organs are subjected to handling and manipulation in the normal course of harvesting, processing, manufacturing, shipping and storage of prostheses. Some specific examples of such bioprostheses include, but are not limited to, porcine heart valves, fetal tissue derived vascular grafts (e.g., from umbilical tissue), fetal neurological tissue, electrically activated muscle blood pumps (e.g., ventricular assist devices), etc. The manipulation of these tissue derived bioprostheses and organ transplants can damage tissues, e.g., by desiccation or abrasive trauma, and thereby adversely affect in vivo biophysical or biochemical properties and reduce the safety and efficacy of the bioprosthesis or organ transplant. Organ and tissue transplants such as hearts, lungs, kidneys, livers, corneas, tendons, etc., can be similarly damaged by the normal manipulation that occurs with harvesting, storing, preparing, processing, shipping and implanting organs, tissues or composite bioprostheses into recipient patients.
It is an object of the present invention to provide improved compositions and methods for protecting tissue and preventing tissue damage in surgery.
It is another object of the present invention to provide improved methods and compositions for protecting human and animal derived tissues and organs during the manipulations that occur during harvesting, processing, storing, shipping and implantation thereof from trauma and damage which can result in impaired organ or tissue function or induce undesirable biological behavior.
Finally, it is an additional object of the present invention to provide improved compositions and methods for protecting those parts of bioprostheses derived from animal or human tissues or organs from trauma and damage during the harvesting thereof and the manufacture, processing, storing, manipulation, shipping and implantation of the bioprostheses, which trauma or damage could result in impaired bioprosthesis function or induce undesirable biological behavior.
The above and other objects are realized by the present invention, one embodiment of which is a method of protecting tissue and preventing tissue damage in surgery comprising providing surfaces involved in surgery with a wet coating of a physiologically acceptable aqueous solution of a hydrophilic, polymeric material prior to manipulation of the tissue during surgery, wherein:
A) the polymeric material is a water-soluble, biocompatible, pharmaceutically acceptable polypeptide, polysaccharide, excluding hyaluronic acid having a molecular weight above about 1,500,000, synthetic polymer, salt, complex or mixture thereof; and
B) the polymeric material has a molecular weight of about 50,000 D or above, and the concentration of the aqueous solution of the polymer is in the range of from about 0.01% to about 15% by weight; the molecular weight and concentration having values such that the aqueous solution is capable of providing wet coatings on the tissue surfaces.
Another embodiment of the present invention is a method of protecting tissue and preventing tissue damage in surgery comprising providing surfaces involved in the surgery with a wet coating of a physiologically acceptable aqueous solution of a hydrophilic, polymeric material prior to manipulation of the tissue during surgery, wherein:
A) the polymeric material is a water-soluble, biocompatible, pharmaceutically acceptable, hyaluronic acid having a molecular weight above about 1,500,000, salt, complex or mixture thereof; and
B) the concentration in the aqueous solution of the hyaluronic acid, complex or salt is in the range of from about 0.01% to less than about 1% by weight, the molecular weight and concentration having values such that the aqueous solution is capable of providing wet coatings on the tissue surface.
Yet another embodiment of the present invention comprises a surgical article, surfaces of which are adapted for contacting tissue surfaces during surgery having a coating thereon formed from one of the compositions described above.
A further embodiment of the present invention relates to a method of protecting from damage tissues or organs during the harvesting thereof from animals or humans, the manufacture therefrom of bioprostheses, and the subsequent manipulations and implantations of the bioprostheses in animals or humans, comprising providing the tissue or organ surfaces with a wet coating of a physiologically acceptable aqueous solution of a hydrophilic, polymer material prior to and during the harvesting, manufacture of bioprostheses, manipulations and implantations thereof, wherein:
A) the polymeric material is a water-soluble, biocompatible, pharmaceutically acceptable polypeptide, polysaccharide, excluding hyaluronic acid having a molecular weight above about 1,500,000, synthetic polymer, salt, complex or mixture thereof; and
B) the polymeric material has a molecular weight of about 50,000 D or above, and the concentration in the aqueous solution of the polymer is in the range of from about 0.01% to about 15% by weight, the molecular weight and concentration having values such that the aqueous solution is capable of providing wet coatings on the surfaces.
A still further embodiment of the invention relates to the above-described coated bioprostheses.
A final embodiment of the invention comprises a method of protecting from damage tissues or organs or parts thereof during the harvesting thereof from animals or humans, the subsequent manipulations and implantations of the tissues or organs or parts thereof in animals or humans, comprising providing the tissue and organ surfaces with a wet coating of a physiologically acceptable aqueous solution of a hydrophilic, polymeric material prior to and during the harvesting, manipulations and implantations thereof, wherein:
A) the polymeric material is a water-soluble, biocompatible, pharmaceutically acceptable polypeptide, polysaccharide, excluding hyaluronic acid having a molecular weight above about 1,500,000, synthetic polymer, salt, complex or mixture thereof; and
B) the polymeric material has a molecular weight of about 50,000 D or above, and the concentration in the aqueous solution of the polymer is in the range of from about 0.01% to about 15% by weight, the molecular weight and concentration having values such that the aqueous solution is capable of providing wet coatings on the surfaces.